Haematopoiesis Flashcards
What is haematopoiesis?
Production of mature blood cells from pluripotent stem cells and haematopoietic stem cells
When does blood production begin?
Day 17 in embryo
Where does blood production begin in utero?
Extraembryonic splanchnic mesoderm surrounding yolk sac
What induces formation of haemangioblastic aggregates?
Mesoderm association with yolk sac
What cell lineages do haemangioblastic aggregates differentiate into?
Endothelial precursor cells
Primitive haematopoietic stem cells
What do the products of haemangioblastic aggregate differentiation form?
Blood islands
What do endothelial precursor cells differentiate into? Through what process do these cells form capillaries?
Endothelial cells
Vasculogenesis
How many waves do HSCs develop in?
2
From what does primitive hematopoiesis occur?
Mesodermal precursors which migrate to yolk sac
When does primitive hematopoiesis begin to make its productions?
Mid to late primitive streak stage
What cells does primitive haematopoiesis produce?
Primitive erythropoietic cells
Primitive macrophages
Primitive megakaryocytes
Describe primitive erythropoietic cells?
Nucleated
Contain embryonic Hb
6x larger than definitive RBCs
Describe primitive macrophages?
‘Mononuclear’ cell
Greater developmental potential
Describe primitive megakaryocytes?
Mature more rapidly
Contain less polyploidy
What is the cell potency of definitive HSCs?
Multipotent
Where do definitive HSCs arise?
A cluster of mesoderm cells which continue development in:
- Placenta
- Aorta-gonad-mesonephros region
Where can additional definitive HSCs arise?
Umbilical and vitelline arteries
One definitive HSCs have formed, where do they migrate to?
Foetal liver
Spleen
Bone marrow (just before birth)
From what do erythroblast progenitors develop from?
Common myeloid precursors
Where do primitive erythrocytes mature?
Bloodstream
How many generations are there between erythroid stem cells and erythrocytes?
At least 5
Where do definitive erythrocytes mature?
Foetal liver
Genes for what types of Hb are expressed by primitive erythrocytes?
Embryonic and adult haemoglobin
What is the difference between types of Hb?
Stability of subunit interference
What is the major site of production of all mature circulating blood in the adult?
Bone marrow
What is the exception to the main site of blood cell production?
T cells produced in thymus:
- Specialised microenvironment required to complete development
What did Samokhvalov et al., (2007) discover regarding haematopoiesis in adults?
Some adult HSCs have extraembryonic origin:
- Migration of haematopoietic stem progenitors from yolk sac to fetal liver and thymus
- Yolk-sac blood islands contain precursors to adult HSCs
What are true HSCs defined by?
Their capacity to long-term reconstitute the haematopoietic system of the adult
What do HSCs in the adult give rise to?
Differentiated progeny
Why do HSCs expand in the fetal liver?
To make up the number of HSCs necessary to sustain haematopoiesis throughout adulthood
Where do HSCs eventually migrate to and when?
Bone marrow cavities of the axial skeleton perinatally
Where can extramedullary erythropoiesis occur in the adult and under what conditions?
Liver or spleen
In severe bone marrow dysfunction
What did Schlitt et al., (1995) report in regards to extramedullary erythropoiesis?
Extramedullary erythropoiesis in the liver and multilineage haematopoiesis by donor-derived cells occurs following liver transplant in adult with normally functioning bone marrow
What type of tissue is bone marrow?
Primary lymphoid
Is bone marrow one of the biggest organs in the body?
Yes
Where is bone marrow found?
In the medullary cavity:
- Formed from interstices of cancellous bone
In what bones is bone marrow found?
Central parts of long bones
Some bones of axial skeleton
What are the three components of bone marrow?
Red marrow
Yellow marrow
Osseous
What parts of bone marrow are active and inactive?
Haematopoietically active = Red marrow
Inactive = Yellow marrow
What percentage of body weight does bone marrow constitute?
~5%
What is the entire bone marrow cavity in the neonate occupied by?
Proliferating haematopoietic cells
What happens to haematopoietic marrow as a child ages?
The regions is happens in contracts centripetally:
- Can occur in phalanges in neonates
- Contracts to only occur in more proximal bones
- Replaced by fatty marrow
In what bones, specifically, does haematopoiesis occur in adults?
Skull Vertebrae Ribs Clavicles Sternum Pelvis Proximal halves of: - Humeri - Femora
Can the volume of marrow cavities occupied with haematopoietic tissue increase with demand?
Yes
What is the stroma of bone marrow?
Framework of: - MSC-originated adipose cells - Stromal cells - Fibroblasts - Macrophages - Blood vessels All interspersed within trabeculae
What is the parenchyma of bone marrow?
Spongy network of haematopoietic cells
How can the bone marrow within vertebral bodies be implicated in IV disc degeneration?
Vertebral bone marrow involved in IV disc nutrition
Fatty conversion reduces supply to IV disc
In what individuals is red marrow abundant in?
Neonates
What cells does red marrow contain?
Haematopoietic cells
Where is red marrow mainly localised?
Metaphyses of long bones
What marrow conversion occurs throughout childhood?
Red marrow to yellow marrow
Where does this marrow conversion occur and continue?
Starts in limbs
Continues proximally
Proceeds into axial skeleton
What are the components of red marrow?
40% water
40% fat
20% protein
What are the components of yellow marrow?
80% fat
15% water
5% protein
Where is yellow marrow found?
Appendicular skeleton of adults:
- Localised in diaphyses and epiphyses of long bones
What percentage of body fat does yellow marrow constitute?
~7%
What are the functions of bone marrow adipocytes (and hence a function of yellow marrow)?
Storage
Secrete adiopokines:
- Leptin
- Adiponectin
What cells share a common origin with bone marrow adipocytes? What is this origin? What does this common origin result in?
Osteoblasts Mesenchymal stem cells Results in competition between alternative differentiation towards either: - Adipogenesis OR - Osteogenesis
WHat HSCs are capable of self-renewal and what do they differentiate into?
Long-term HSCs
Differentiate into short-term HSCs
What can short-term HSC differentiate into?
Common lymphoid progenitor
Common myeloid progenitor
What do common myeloid progenitors differentiate into?
A common erythroid/megakaryocyte progenitor (MEP)
Granulocyte/macrophage progenitor (GMP) cells
What is the life span of an erythrocyte/RBC?
~120 days
How do RBCs appear?
Anucleated
Biconcave disc
What is the main function of RBCs?
Gas exchanged:
- Transport oxygen from lungs to tissues
- Transport CO2 from tissues to lungs
How do RBCs withstand shear during circulation?
Specialised membrane:
- Has typical lipids, proteins and carbohydrates of a plasma membrane
- Also has a cytoskeleton formed of cross-linked proteins
How are old RBCs destroyed?
Spleen by trabecular arrangement
OR
Engulfed by macrophages
What does the shape of a RBC allow?
Provides high flexibility for passages through small-diameter capillaries
What are the general functions of leukocytes/WBCs?
Defend against pathogens
Remove:
- Damaged cells
- Toxins
In terms of cells structure and contents, how do WBCs differ from RBCs generally?
WBCs are nucleated
WBCs contain other organelles
What are the two groups of leukocytes?
Granulocytes
Agranulocytes
What do both types of leukocytes contain?
Secretory vesicles
Lysosomes
How are leukocytes classified into the two groups?
By what is visible under the light microscope
What are the granulocytes?
Eosinophils
Neutrophils
Basophils
What are the agranulocytes?
Monocytes
Lymphocytes
What are the only type of WBC which are specific?
Lymphocytes
Why are the other types of leukocytes non-specific?
They are activated by various stimuli
How do eosinophils appear?
Bi-lobed nucleus
Granules stain bright red
What are the functions of eosinophils?
Attack foreign bodies by releasing toxins (nitric oxide; cytotoxic enzymes)
Engulf:
- Smaller bacteria
- Cell debris
Also restrict the inflammatory actions of:
- Neutrophils
- Mast cells
What colour do basophil granules stain?
Blue
What do basophils contain?
Heparin
Histamines
What are the functions of basophils?
Release heparin and histamines at injury site resulting in:
- Vasodilatation
- Prevention of blood clotting
What cells are basophilic functions similar to?
Mast cells
How do neutrophils appear?
Polymorphous nucleus
Many small granules
Larger granules
What do the larger azurophilic granules in neutrophils contain?
Enzymes
What is the life span of a neutrophil?
10 days
What are the functions of neutrophils?
Engulf foreign material:
- Engulfed bacteria fused with lysosomes = Destruction
Release prostaglandins = Inflammation
How do monocytes appear?
Kidney-shaped nuclei
Largest nucleocyte
What is the life span of monocytes in the blood?
3 days
Upon activation, what do monocytes develop into?
Macrophages
What are the functions of activated monocytes (aka macrophages)?
Phagocytose: - Large cells - Foreign objects Release chemokines: - Attract other WBCs to site of injury
What are the least abundant WBCs?
Basophils
What are the most abundant WBCs?
Neutrophils
What are the most abundant agranulocytes?
Lymphocytes
What are the general functions of lymphocytes?
Specific immune response to infection
Regulate inflammation
What are the three types of lymphocytes?
T cells
B cells
NK cells
What are the types of T cells and their functions?
Cytotoxic T cells - Attack foreign cells
Helper T cells - Activate B cells
Suppressor T cells - Inhibit T and B cell activity
What do active B cells differentiate into and produce?
Plasma cells which produce and release antibodies
What do NK cells do?
Recognise foreign cells
Attack by attaching onto target cells:
- Release vesicles which cover cell membrane
- Vesicles release perforin
- Perforin destroys foreign cell membrane
From what do platelets originate?
As fragments of megakaryocytes after cell shearing during circulation
What is the life span of a platelet?
10 days
How does a platelet shape change after activation?
Changes from round discs to a sphere with dendritic extensions
What are the functions of platelets?
Contain secretory granules:
- Secrete various proteins responsible for reinforcing platelet aggregation and platelet-surface coagulation reactions
What is reconversion?
The reverse of the natural conversion process
The replacement of yellow marrow by haematopoietic cells
What non-medical conditions can result in reconversion?
Cigarette smoking
Doing sports with a high oxygen debt
What medical conditions can result in reconversion?
Obesity and related respiratory disorders
Diabetes
Chronic conditions related to asthma
Patients treated with haematopoietic growth factors
When does reconversion occur?
When haematopoietic capacity of existing red marrow stores is exceeded
What MRI features indicate reconversion?
Symmetry of changes
Changes do not extend beyond growth plate:
- Sparing articular ends of bones
What did bone marrow biopsies in smokers show? (Poulton et al.)
Increased cellularity
Modest increase in maturo granulopoietic cells
What is the potential explanation for reconversion in smokers?
Tissue hypoxia and increased carboxyhaemoglobin and resultant stimulation of erythrocyte production
What are the limitations of the Poulton et al. study on reconversion in smokers?
Any red marrow in atypical locations was considered reconversion
Didn’t take into account that not all conversion may have occurred by age 25
What is a neoplastic marrow infiltrate disorder?
Fatty marrow replaced with neoplastic tissue
What neoplastic disease can infiltrate marrow?
Leukaemia
Lymphoma
Multiple myeloma
Metastatic disease
Why do metastases more commonly localise in red marrow than yellow marrow?
Richer blood supply
Where is the most common site of metastatic disease to the marrow?
Vertebral column (69%)
What is a fibrotic marrow infiltrate disorder?
Fatty marrow replaced by fibrotic tissue
Infiltration occurs as a result of fibrosis
What is osteomyelitis? What does it result in?
Infiltration of bone marrow by inflammatory cells
Results in:
- Increased extracellular water/fluid
What is marrow infarction?
Obstruction of medulla
What can result in marrow infarction?
Malignant infiltration of marrow with consequent elevation of intraosseous pressure OR Secondary to: - Chemotherapy - Steroid injection OR Sickle cell disease
What is the pathology of myeloid depletion?
Loss of normal red marrow:
- Acellular or Hypocellular
- Yellow marrow fills marrow space (fat and fibrosis)
What are the pathological sequelae of myeloid depletion?
Oedema
Vascular congestion
Diminished haematopoiesis
What can cause myeloid depletion?
Viral infections
Medications
Chemotherapy/Radiotherapy
Idiopathic/Unknown
Within how many years of radiotherapy can the marrow recovery after myeloid depletion?
1-2 years
What is myelofibrosis?
Replacement of normal marrow cells by fibrotic tissue
What usually causes myelofibrosis?
Chemotherapy
Radiotherapy
Can be a primary disorder
What is bone marrow hyperplasia?
The process of repopulation of yellow marrow by red marrow by reconversion mechanisms
What causes bone marrow hyperplasia?
Increased demand for haematopoiesis
Where does reconversion occur in bone marrow hyperplasia?
Begins in vertebrae and flat bones of pelvis
Progresses to long bones
(ie opposite pattern to physiological conversion with age)
What are the causes of bone marrow hyperplasia (reconversion)?
Severe chronic anaemia in: - Sickle cell disease - Thalassaemia - Hereditary spherocytosis Marrow replacement by neoplastic cells Chemotherapy Increased oxygen demands
What cell lineages does bone marrow hyperplasia affect?
Can affect all lineages
OR
Just an individual cell line:
- Will affect myeloid/erythroid cell ratio
What is hypoplasia?
Underdevelopment of a tissue of organ
What is bone marrow hypoplasia?
Replacement of red marrow by yellow marrow by myeloid depletion mechanisms
What can cause bone marrow hypoplasia?
Typically chemotherapy/radiotherapy regimes Also: - Viral infections - Other medications - Unknown cause
How does bone marrow hypoplasia progress?
Initially bone marrow oedema Decrease haematopoiesis Finally red marrow replacement by: - Adipose tissue - Fibrosis
What is thalassaemia?
Imbalanced globin chain production due to diminished or absent production of one or more globin chains
What is the pathogenesis of thalassaemia?
Excess globin chains form tetramers and precipitate within RBCs:
- Leads to chronic haemolysis in bone marrow and peripheral blood
What does the severity of thalassaemia depend on?
Type of mutation or deletion
What are the subgroups of thalassaemia?
Alpha
Beta
What process occurs in thalassaemia and why?
Extramedullary haematopoiesis
Due to chronic overproduction of erythrocytes
How can thalassaemia affect the vertebral column? (Aydingoz et al., 1997)?
Thalassaemia results in extramedullary haematopoiesis
Extramedullary haematopoiesis results in hyperplasia of haematopoietic tissue
Spinal cord is compressed by epidural extramedullary haematopoietic tissue
